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review article
Mechanisms of Disease
Major Depressive DisorderR.H. Belmaker, M.D., and Galila Agam, Ph.D.
From Ben Gurion University of the Negev, Beersheba, Israel. Address reprint requests to Dr. Belmaker at Beersheba Mental Health Center, P.O. Box 4600, Beersheba, Israel, or at [email protected].
Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emo-tions dissipates, and it is disproportionate to their cause. Classic severe states
of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events.1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sex-ual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These chang-es must last a minimum of 2 weeks and interfere considerably with work and fam-ily relations. On the basis of this broad definition, the lifetime incidence of depres-sion in the United States is more than 12% in men and 20% in women.2 Some have advocated a much narrower definition of severe depression, which they call melan-cholia or vital depression.3
A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depres-sive disorder overlap, a history of mania defines a distinct illness termed bipolar dis-order.4
Depression is a heterogeneous disorder with a highly variable course, an inconsis-tent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major de-pression.
Gene tic s
Studies comparing concordance rates for major depression between monozygotic and dizygotic twins suggest a heritability of about 37%,5 which is much lower than the heritability of bipolar disorder or schizophrenia. Some aspects of the normal person-ality, such as avoidance of harm, anxiousness, and pessimism, are also partly heritable.6 Kendler et al.7 showed that although depression is due in part to heritable depression-prone personality traits, it is also the result of heritable factors that are independent of personality. Early-onset, severe, and recurrent depression may have a higher heri-tability than other forms of depression.8 It is clear from studies of families that major depression is not caused by any single gene but is a disease with complex genetic fea-tures. Studies of pedigrees with multiple cases of major depression have identified chromosomal regions with linkage to the disorder, and some of these loci have been replicated in more than one study, although no single chromosomal region has been replicated in every family study of genetic linkage in depression. Holmans et al.9 found
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evidence of linkage of recurrent, early-onset de-pression to chromosome 15q25-q26, but the pop-ulation attributable risk was small.
No specific molecular risk factor has been reli-ably identified. One common polymorphic variant of the serotonin-transporter–linked polymorphic region (5-HTTLPR), which affects the promoter of the serotonin-transporter gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain.10 Some studies have shown that this polymorphism confers a predis-position to depression,11 but it also confers a pre-disposition to an anxious and pessimistic person-ality.10 Brain imaging reveals functional differences in emotion-related areas of the brain among car-riers of the different common polymorphisms of 5-HTTLPR,12 although a direct relation to depres-sion is unclear. In a large, prospective epidemio-logic study, Caspi et al.13 found that 5-HTTLPR predicted depression only in association with de-fined life stresses. Some environmental factors could confer a predisposition to depression by af-fecting the genome epigenetically — for example, increased maternal care in rodents causes an epi-genetic change in the promoter region of the glu-cocorticoid-receptor gene.14
The Monoa mine-Deficienc y H y po thesis
The noradrenergic and serotonergic systems orig-inate deep in the brain and fan out over almost the entire brain, suggesting a system capable of modulating many areas of feeling, thinking, and behaving. The early antidepressants blocked the reuptake of norepinephrine and serotonin by the presynaptic neuron. The immediate effects of this pharmacologic action are to increase the availabil-ity of norepinephrine and serotonin in the synapse and to increase stimulation of the postsynaptic neuron. Inhibitors of the enzyme monoamine oxi-dase were also discovered to have antidepressant properties. This enzyme catabolizes norepineph-rine and serotonin in their respective presynaptic neurons, and such inhibition could be expected to increase the availability of neurotransmitters. These discoveries led to a major theory of depression known as the monoamine-deficiency hypothesis. Numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal fluid, as well as postmortem studies of the brains of patients with depression, have yet to identify the
purported deficiency reliably. However, a newly dis-covered form of the enzyme tryptophan hydroxy-lase, designated TPH-2, is specific to the brain15 and could explain why previous postmortem stud-ies of total enzyme activity did not show differ-ences in tryptophan hydroxylase activity between patients with depression and controls.16 A recent positron-emission tomographic study using a li-gand for brain monoamine oxidase showed a 30% increase of the enzyme in a subgroup of patients with depression.17 A study measuring differences in monoamine metabolites between the internal jugular vein and the brachial artery showed lower production by the brain of norepinephrine metabo-lites in patients with depression than in controls.18 The monoamine-deficiency hypothesis continues to stimulate research whenever a new technical window into the brain is opened.
Serotonin and norepinephrine can be depleted experimentally in humans by oral treatments.19 A drink containing all amino acids except trypto-phan stimulates the liver to synthesize proteins and rapidly depletes the plasma (and therefore the brain) of tryptophan. Tryptophan is rate-limiting for serotonin synthesis in the brain. Such oral tryptophan depletion does not induce depression in healthy subjects but will cause a relapse of de-pression in patients who have been successfully treated with a serotonin-reuptake inhibitor.19 Sim-ilarly, α-methyl paratyrosine inhibits tyrosine hy-droxylase, the rate-limiting step in catecholamine synthesis. Treatment with α-methyl paratyrosine does not induce depression in normal subjects but will induce a relapse in patients who have been treated successfully with a norepinephrine-reup-take inhibitor.19 These findings suggest that nor-epinephrine and serotonin have critical roles in the mechanisms of these treatments of depression but that additional neurochemical factors are neces-sary to cause depression.
Because direct measurements of monoamine neurotransmission did not yield definitive findings in relation to depression, the downstream effects of monoamine neurotransmission were explored (Fig. 1). The serotonin-1B receptor is located pre-synaptically and regulates the release of serotonin by feedback inhibition. Postmortem studies show that the levels of p11, a protein that enhances the efficiency of serotonin-1B receptor signaling, are decreased in the brains of patients with depres-sion.20 The serotonin-1A receptor is located both presynaptically and postsynaptically to regulate
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n engl j med 358;1 www.nejm.org january 3, 2008 57
serotonin function (Fig. 1). The receptor can be evaluated in patients with depression by injecting specific agonists and measuring specific neuro-endocrine responses, such as elevation of the pro-lactin level.21 Results suggest that the sensitivity of this receptor is reduced in patients with depres-sion.21 The α2-noradrenergic receptor, which is usually presynaptic, modulates norepinephrine re-lease by feedback inhibition (Fig. 1). Heightened receptor sensitivity has been described in patients with depression,22 which is consistent with re-duced norepinephrine release.
It is conceivable that the second-messenger sys-tems for serotonergic and noradrenergic neuro-transmission malfunction in depression, and for this reason the phosphatidylinositol and cyclic AMP second-messenger systems have been exten-sively evaluated. Reduced inositol levels have been found in postmortem studies of the brains of per-sons who have died by suicide23 and in magnetic resonance spectroscopic studies of the frontal cor-tex in patients with depression.24 A blunted cyclic AMP response to stimulation was found in post-mortem studies of the brains of patients with de-pression.25 These reductions in second-messenger function may impair neurotransmitter function even without changes in monoamine levels or re-ceptor numbers. These data indirectly support elaborations of the original monoamine-deficiency hypothesis of depression (Fig. 1).
G proteins that mediate signaling between re-ceptors and second-messenger systems have also been investigated in patients with depression, both in postmortem studies of the brain26 and in stud-ies of peripheral-blood cells.27 Although these systems are clearly affected, no consistent picture has emerged because there are numerous forms of G proteins that vary in different areas of the brain. The cyclic AMP response element–binding protein (CREB) is a transcription factor affected by cyclic AMP in the cell. In an animal model of de-pression, rats with overexpression of CREB in the dentate gyrus behaved similarly to rats treated with antidepressants, but the opposite effect was found when CREB was overexpressed in the nu-cleus accumbens.26,28 Thus, the role of CREB in depression is specific to the region of the brain. Most but not all studies show that long-term treat-ment with antidepressants stimulates CREB func-tion, possibly depending on the type of drug and the dosage.28 Levels of CREB and phospho-CREB were reduced in postmortem studies of the cor-
texes of patients who had a major depressive disorder and had not taken antidepressants, as compared with controls.26,28 Many studies of sec-ond-messenger systems and transcription factors in depression were inspired by the belief that it takes several weeks before antidepressant treat-ment has an effect; consequently, the studies were designed to detect time-dependent biochemical changes in the cell. New meta-analyses suggest that antidepressant effects begin rapidly, howev-er,29 thereby supporting the classic monoamine-deficiency hypothesis.
A strong point of the monoamine theory has been its predictive power. Almost every compound that has been synthesized for the purpose of in-hibiting norepinephrine or serotonin reuptake has been proved to be a clinically effective antidepres-sant. A behavioral model of depression has been developed in which a rodent is placed in a glass cylinder filled with water, the sheer wall offering no chance of escape. The animal struggles for a while and then floats passively (the forced swim test). A single prior injection of antidepressant in-creases the struggling time; results in this model have excellent predictive validity for new antide-pressants. Other animal models have been devel-oped by selective breeding of rats for depression-like behavior, and these genetically susceptible rodents also have a response to antidepressants.30 Still other models that can be studied biochemi-cally induce depression with the use of long-term mild stress or learned helplessness. However, no animal model of depression captures the periodic change of behavior into and out of depression that is seen in patients with depression.
Molecular techniques such as gene knockout partially support the monoamine theory of depres-sion. The serotonin-reuptake–transporter knock-out mouse is excessively anxious and characterized by increased immobility in the forced swim test.31 This effect is similar to that of the low-activity polymorphic variant of the serotonin receptor on human personality10 but is the opposite of the ex-pected effects of serotonin-reuptake–inhibitor an-tidepressants. However, this inconsistency could be explained by the difference between a chron-ic monoamine abnormality during brain develop-ment31 and the hypothesized acute monoamine depletion in an adult with depression. Table 1 shows the effects in mice of knocking out genes related to monoamine neurotransmitters.
The effects of stimulants on mood indirectly
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support the monoamine-deficiency hypothesis of depression and show that mood can be altered rapidly. Cocaine and amphetamines are powerful releasers of monoamines into the synapse as well as inhibitors of reuptake. Their mood-elevating effects are immediate, but in patients with severe depression they have often been reported to cause agitation rather than relief of depression. This finding could reflect the ability of these stimulants to deplete the presynapse of monoamines and thus cause a “crash” into depression. Recent studies support the theory that an acute response to a single dose of amphetamine predicts a patient’s longer-term response to monoamine-reuptake in-hibitors.46
The role of dopamine deficiency in depression is suggested by the frequency of depression in pa-tients with Parkinson’s disease and the effect of reserpine, which depletes serotonin, norepineph-rine, and dopamine, causing a hypoactive state in animals. The antidepressant agent buproprion in-hibits the reuptake of dopamine. Some direct do-pamine-receptor agonists, such as pramipexole, have been reported to be efficacious in the treat-ment of depression, even though they were devel-oped for Parkinson’s disease.47
A major liability of the monoamine-deficiency hypothesis is its derivation from the mechanism of currently available antidepressants. Approxi-mately two thirds of patients have a clinical re-sponse to these agents, whereas one third have a response to placebo.48 Perhaps the mechanism of depression is not related to monoamines in two of three cases.
S tr ess, the H y po th a l a mic –Pi t ui ta r y–A dr ena l A x is,
a nd Grow th Fac t or s
Stress49 is perceived by the cortex of the brain and transmitted to the hypothalamus, where cortico-tropin-releasing hormone (CRH) is released onto pituitary receptors. This stimulus results in the se-cretion of corticotropin into plasma, stimulation of corticotropin receptors in the adrenal cortex, and release of cortisol into the blood. Hypothalam-ic cortisol receptors respond by decreasing CRH production to maintain homeostasis (Fig. 2).
There is considerable evidence that cortisol and its central releasing factor, CRH, are involved in depression.50,51 Patients with depression may have elevated cortisol levels in plasma,38 elevated
CRH levels in cerebrospinal fluid,50 and increased levels of CRH messenger RNA and protein in limbic brain regions.50 In studies using dexa-methasone to evaluate the sensitivity of the hypo-thalamus to feedback signals for the shutdown of CRH release, the normal cortisol-suppression re-sponse is absent in about half of the most se-
Figure 1 (facing page). The Monoamine-Deficiency Hypothesis Extended.
The monoamine hypothesis of depression postulates a deficiency in serotonin or norepinephrine neurotrans-mission in the brain. Monoaminergic neurotransmis-sion is mediated by serotonin (5-hydroxytryptamine 1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or norepinephrine (noradrenaline) released from presyn-aptic neurons (serotonergic neuron, shown on the left side, and noradrenergic neuron, shown on the right side [condensed virtually]). Serotonin is synthesized from tryptophan, with the first step in the synthetic pathway catalyzed by tryptophan hydroxylase; norepi-nephrine is synthesized from tyrosine, with the first step catalyzed by tyrosine hydroxylase. Both mono-amine transmitters are stored in vesicles in the presyn-aptic neuron and released into the synaptic cleft, there-by affecting both presynaptic and postsynaptic neurons. Cessation of the synaptic action of the neu-rotransmitters occurs by means of both reuptake through the specific serotonin and norepinephrine transporters and feedback control of release through the presynaptic 5-HT1A and 5-HT1B regulatory autore-ceptors for serotonin and the α2-noradrenergic autore-ceptors for norepinephrine. Monoamine oxidase A (MAO-A) catabolizes monoamines presynaptically and thereby indirectly regulates vesicular content. The pro-tein p11, which interacts with 5-HT1B receptors, in-creases their function. Postsynaptically, both serotonin and norepinephrine bind two kinds of guanine nucleo-tide triphosphate–binding protein (G protein)–coupled receptors: cyclic AMP (cAMP)–coupled receptors, which activate adenylate cyclase (AC) to generate cAMP, and phosphatidylinositol (PI)–coupled recep-tors, which activate phospholipase C (PLC). PLC gener-ates inositol triphosphate (IP3) and diacylglycerol (DAG); cAMP activates protein kinase A (PKA), and IP3 and DAG activate protein kinase C (PKC). The two pro-tein kinases affect the cAMP response element–bind-ing protein (CREB). Findings in patients with depres-sion that support the monoamine-deficiency hypothesis include a relapse of depression with inhibi-tion of tyrosine hydroxylase or depletion of dietary tryptophan, an increased frequency of a mutation af-fecting the brain-specific form of tryptophan hydroxy-lase (TPH-2), increased specific ligand binding to MAO-A, subsensitive 5-HT1A receptors, malfunction-ing 5-HT1B receptors, decreased levels of p11, poly-morphisms of the serotonin-reuptake transporter asso-ciated with depression, an inadequate response of G proteins to neurotransmitter signals, and reduced lev-els of cAMP, inositol, and CREB in postmortem brains.
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n engl j med 358;1 www.nejm.org january 3, 2008 59
verely depressed patients.52 Antidepressant-induced clinical remission is accompanied by reversal of some of these abnormalities.52
Adults with a history of physical or sexual abuse as children have increased levels of CRH in cerebrospinal fluid.53 Adult rodents that were sepa-rated from their mothers or abused as pups show increased immobility in the forced swim test, which is reversed by antidepressant treatment.54 Mice with region-specific knockout of the gluco-corticoid receptor at an adult age have increased
activity of the hypothalamic–pituitary–adrenal axis and increased immobility in the forced swim test, both of which are reversed by antidepressants.55 Increased levels of monoamines in the synapse affect the hypothalamic–pituitary–adrenal axis56 and reverse some of the long-term effects of stress.56 It is possible that antidepressants relieve depression by reducing the secondary stress caused by a painfully dispirited mood rather than by di-rectly elevating mood. An antistress mechanism could explain the general usefulness of antidepres-
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sants for a wide variety of psychiatric conditions, including panic disorder, post-traumatic stress disorder, bulimia, premenstrual syndrome, and obsessive–compulsive disorder. CRH-receptor an-tagonists show antidepressant activity in animal models,57 but the results of large clinical trials have been disappointing. A compound that blocks the glucocorticoid receptor has been reported to
be efficacious in depression, but only the most severe and psychotic type.58
A single test for the cortisol level in blood does not contribute to the diagnosis of depression, since levels of cortisol vary markedly in a circadian rhythm38 and because the overlap between values in patients and those in controls is considerable. Mild stress induced in the laboratory, such as
Figure 2. The Hypothalamic–Pituitary–Cortisol System in Depression.
The hypothalamic–pituitary–cortisol hypothesis of depression postulates that abnormalities in the cortisol response to stress may underlie depression. The black arrows show that in response to stress, which is perceived by the brain cortex and the amygdala and transmitted to the hypothalamus, corticotropin-releasing hormone (CRH) is released, inducing the anterior pituitary gland to secrete corticotropin into the bloodstream. Corticotropin stimulates the ad-renal cortexes to secrete the glucocorticoid hormone cortisol. The red lines show that cortisol, in turn, induces feed-back inhibition in the hypothalamus and the pituitary, suppressing the production of CRH and corticotropin, respec-tively. Findings in patients with depression that support the hypothalamic–pituitary–cortisol hypothesis include the following: cortisol levels are sometimes increased in severe depression, the size of the anterior pituitary and adrenal cortex is increased, and CRH levels in the cerebrospinal fluid and CRH expression in the limbic brain regions are in-creased. Hippocampal size and the numbers of neurons and glia are decreased, possibly reflecting reduced neuro-genesis due to elevated cortisol levels or due to reduced brain-derived neurotrophic factor.
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Tabl
e 2.
Add
ition
al B
iolo
gic
Theo
ries
of t
he P
atho
phys
iolo
gy o
f Dep
ress
ion.
*
Theo
rySu
ppor
ting
Evid
ence
Con
trad
icto
ry E
vide
nce
Alte
red
glut
amat
ergi
c
neur
otra
nsm
issi
onG
luta
mat
e an
d gl
utam
ine
leve
ls in
the
pref
ront
al c
orte
x ar
e re
duce
d91G
luta
mat
e le
vels
in th
e oc
cipi
tal c
orte
x ar
e in
crea
sed92
,93
Intr
aven
ous
keta
min
e, a
n N
MD
A a
ntag
onis
t, in
duce
s ra
pid,
sus
tain
ed a
nti-
depr
essa
nt e
ffect
94K
etam
ine
bind
s to
hig
h-af
finity
-sta
te D
2 do
pam
ine
rece
ptor
s95
Cor
tical
mes
seng
er R
NA
leve
ls o
f glu
tam
ate
tran
spor
ters
and
of t
he e
nzym
e th
at c
onve
rts
glut
amat
e to
glu
tam
ine
are
redu
ced96
It
is n
ot c
lear
whe
ther
ant
idep
ress
ants
affe
ct A
MPA
rec
epto
rs in
the
brai
n97
Red
uced
GA
BA
ergi
c
neur
otra
nsm
issi
onLe
vels
of G
AB
A in
pla
sma,
cer
ebro
spin
al fl
uid,
the
dors
olat
eral
pre
fron
tal
cort
ex, a
nd th
e oc
cipi
tal c
orte
x ar
e re
duce
d91-9
3G
AB
A o
ccur
s in
mor
e th
an 3
0% o
f bra
in s
ynap
ses,
sug
gest
ing
nons
peci
ficity
GA
BA
-mod
ulat
ing
agen
ts h
ave
effe
cts
in a
nim
al m
odel
s of
dep
ress
ion98
Ther
e is
a la
ck o
f diff
eren
ce in
pre
fron
tal c
orte
x G
AB
A le
vels
on
MR
S in
de-
pres
sion
99
Ant
idep
ress
ants
affe
ct G
AB
Aer
gic
func
tion98
G
AB
A n
euro
tran
smis
sion
may
be
rela
ted
to s
ympt
oms
of a
nxie
ty in
de
pres
sion
GA
BA
neu
ron
imm
unor
eact
ivity
is r
educ
ed in
the
pref
ront
al c
orte
x100
Abn
orm
al c
irca
dian
rh
ythm
sSl
eep
depr
ivat
ion
and
light
ther
apy
have
ant
idep
ress
ant e
ffect
s101,
102
The
asso
ciat
ion
betw
een
cloc
k-re
late
d ge
nes
and
depr
essi
on is
inco
nsis
-te
nt10
3So
me
patie
nts
with
dep
ress
ion
have
cir
cadi
an a
bnor
mal
ities
of m
ood,
sle
ep,
tem
pera
ture
, and
neu
roen
docr
ine
secr
etio
n104
Rod
ents
act
ive
duri
ng th
e da
y be
com
e de
pres
sed
whe
n da
ylig
ht is
sho
rt-
ened
105
Def
icie
nt n
euro
ster
oid
synt
hesi
sC
hole
ster
ol le
vels
are
low
in p
lasm
a an
d th
e br
ain
duri
ng d
epre
ssio
n106
The
findi
ngs
in s
chiz
ophr
enia
are
sim
ilar10
7
DH
EA h
as a
ntid
epre
ssan
t effe
cts
in p
atie
nts
with
dep
ress
ion10
8 N
euro
ster
oids
(ne
uroa
ctiv
e st
eroi
ds in
the
brai
n th
at m
odul
ate
neur
otra
ns-
mitt
er r
ecep
tors
) m
ostly
affe
ct m
emor
y an
d sl
eep
Impa
ired
end
ogen
ous
opi-
oid
func
tion
δ-O
pioi
d–re
cept
or a
goni
sts
have
ant
idep
ress
ant-
like
effe
cts
in r
oden
ts a
nd
up-r
egul
ate
leve
ls o
f BD
NF
in th
e br
ain10
9A
lthou
gh e
arly
rep
orts
sug
gest
ed th
at o
piat
es m
ay b
e ef
fect
ive
in tr
eatin
g de
-pr
essi
on,11
0 dat
a fr
om la
rge,
con
trol
led,
ran
dom
ized
tria
ls a
re la
ckin
g
Cap
acity
for
cort
ical
μ-o
pioi
d–re
cept
or b
indi
ng is
dec
reas
ed in
res
pons
e to
su
stai
ned
sadn
ess11
1
Mon
oam
ine–
acet
ylch
olin
e im
bala
nce
Dep
ress
ed m
ood
can
be in
duce
d in
hum
ans
by a
dmin
istr
atio
n of
phy
sost
ig-
min
e, a
n ac
etyl
chol
ines
tera
se in
hibi
tor11
2M
ecam
ylam
ine,
a n
icot
inic
ace
tylc
holin
e re
cept
or a
ntag
onis
t, re
duce
d sy
mp-
tom
s of
dep
ress
ion11
3
Nic
otin
ic a
cety
lcho
line
rece
ptor
ant
agon
ists
pot
entia
te a
ntid
epre
ssan
ts11
4M
any
antid
epre
ssan
ts a
re n
ot a
ntic
holin
ergi
c
Cyt
okin
e-m
edia
ted
cros
s-ta
lk b
etw
een
the
im-
mun
e sy
stem
and
the
brai
n
Dep
ress
ion
is c
omm
on in
infe
ctio
us a
nd a
utoi
mm
une
dise
ases
115
Mos
t stu
dies
are
cor
rela
tive11
6
Expo
sure
to c
ytok
ines
indu
ces
depr
essi
ve s
ympt
oms,
and
cyt
okin
e se
cret
ion
is in
crea
sed
in m
ajor
dep
ress
ion11
5 C
ytok
ine-
indu
ced
depr
essi
ve s
ympt
oms
are
tem
pora
ry a
nd n
ot r
eplic
ated
in
all s
tudi
es11
7
Ant
idep
ress
ants
hav
e an
tiinf
lam
mat
ory
effe
cts11
5Su
bsta
nce
P an
tago
nist
s ar
e no
t the
rape
utic
in d
epre
ssio
n
Cyt
okin
es a
ffect
the
hypo
thal
amic
–pitu
itary
–adr
enal
axi
s an
d m
ono-
amin
es11
5
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stress associated with mental arithmetic calcula-tions or simulated public speaking, results in greater changes in plasma cortisol levels than most reported differences between the values in patients with depression and those in controls.38 It is possible that chronic mild elevations of cor-tisol, especially at night, when cortisol levels in normal subjects are very low, have a pathogenic role in depression. It is also possible that periph-eral cortisol elevations are only a reflection of central disturbances in CRH signaling, which me-diate the effects of environmental stress on mood.59 A major liability of the hypothalamic–pituitary–adrenal axis theory of depression is the difficulty of defining the relationship of stress to depres-sion. Some patients have a single lifetime depres-sive episode, whereas a larger proportion have a recurrent or even chronic course. Various types of acute stress, early childhood trauma, or long-term psychosocial problems may be involved and may lead to different responses of the stress sys-tem. Stress may be causative in some cases and secondary to depressed mood in others.
Severe stress in rodents does not necessarily model the common stresses of childhood. The association of abuse in childhood with psycho-pathologic disorders, including depression, in adulthood could be due to common factors link-ing family perpetrators of abuse and their victims, including not only shared genes but also a shared environment of poverty, poor nutrition, and poor prenatal care. Depression is not uncommon in people with no psychosocial risk factors. Most patients treated for depression have no evidence of hypothalamic–pituitary–adrenal dysfunction, just as most such patients have no direct evidence of brain monoamine deficiency.
The classic teaching is that neurons do not di-vide in the adult mammalian brain, but studies have shown that neurogenesis occurs in several areas of the brain, especially the hippocampus. Neurogenesis is more prominent in rodents than in primates,60 and some have questioned whether it occurs in the human cortex.61 Elevated levels of glucocorticoids can reduce neurogenesis, and this has been suggested as a mechanism for the de-creased size of the hippocampus on magnetic resonance images of the brain in many patients with depression.62 In postmortem studies of pa-tients with depression, cell loss in the subgenual prefrontal cortex, atrophy in the dorsolateral pre-frontal cortex and the orbitofrontal cortex, and Th
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increased numbers of cells in the hypothalamus and the dorsal raphe nucleus have been reported.63 These effects resemble the atrophic changes in the brain in patients with Cushing’s disease64 and in rodents treated with glucocorticoids.65 However, cortisol elevations in depression are much lower than in Cushing’s disease.
Restraint in a small container induces stress in rodents, suppressing neurogenesis, and this effect is countered by antidepressant treatment.66 An-tidepressants also enhance neurogenesis in non-human primates.67 Santarelli et al.68 irradiated the hippocampus in mice and abolished neurogene-sis. They found that the radiation also abolished the ability of the animals to respond behaviorally to antidepressant treatment in the forced swim test, but this phenomenon does not occur in every mouse strain studied.69 Henn and Vollmayr sum-marized other studies providing evidence that de-creased neurogenesis is a result of stress and anxiety but may not be behaviorally relevant.70 The relevance of animal models of neurogenesis to clinical studies of depression has been questioned by analogy with studies of neuroprotection strat-egies in stroke, for which numerous findings in animal models have not been replicated in hu-man studies.71
Brain-derived neurotrophic factor (BDNF), a neurotrophic peptide, is critical for axonal growth, neuronal survival, and synaptic plastic-ity,72 and its levels are affected by stress73 and cortisol.74 A postmortem study of patients with depression who had committed suicide showed that BDNF was reduced in the hippocampus.75 Antidepressant drugs and electroconvulsive thera-py up-regulate BDNF and other neurotrophic and growth factors75,76; a single bilateral infusion of BDNF into the dentate gyrus has antidepressant-like effects.77 One study showed that the hippo-campus was smaller than normal in patients with depression who carried a met166 BDNF allele.78 In an animal model of depression, epigenetic his-tone methylation mediated down-regulation of BDNF transcripts and antidepressant treatment reversed this effect.79 These studies suggest that BDNF is the link among stress, neurogenesis, and hippocampal atrophy in depression. However, a genetic association of the BDNF val166met poly-morphism with depression has not been replicated in most studies,74 and BDNF may be related not only to depression but to multiple psychiatric dis-orders.74 BDNF-knockout mice have behaviors un-
related to depression.45 Reduced BDNF levels in the peripheral blood of patients with depression seem to derive almost entirely from blood plate-lets,80 and many artifacts must therefore be con-sidered in interpreting these findings. Inflamma-tion in the brain and some neurotoxins increase brain BDNF levels, suggesting that the actions of BDNF are not uniformly therapeutic.81 Castrén82 has proposed that antidepressant treatments may increase synaptic sprouting and allow the brain to use input from the environment more effec-tively to recover from depression. This hypothe-sis highlights the role that cognition may play in depression and suggests that biochemical mech-anisms may be nonspecific.
Strong epidemiologic data point to an associa-tion between major depressive disorder and in-creased cardiovascular morbidity and mortality.83 In many patients, cardiovascular disorders precede depression, and in others, depression precedes the cardiovascular disorder. Both n−3 fatty acid defi-ciency84 and elevated plasma homocysteine levels85 have been implicated in cardiovascular disease and in depression. Elevated cortisol levels in depres-sion could increase the risk of coronary artery disease, since cortisol increases visceral fat.64,86 Antidepressant treatment increases the survival rate among patients who become depressed after coronary occlusion.86 Endothelial-cell signaling plays a crucial role in brain neurogenesis,87 and these cells secrete BDNF; thus, both depression and cardiovascular disease could be examples of an endothelial disorder. Signs of inflammatory processes have been described in major depres-sion88 and in cardiovascular disease. Some data suggest that exercise has protective or therapeu-tic effects in depression.89 Rodent models support this possibility.90
O ther Possible Mech a nisms
Table 2 summarizes possible pathophysiological mechanisms of depression other than those based on the monoamine-deficiency hypothesis or the roles of stress, cortisol, and neurogenesis. Many of these other proposed mechanisms have also been implicated in psychiatric and neurologic dis-orders other than depression. Since the compo-nents of the brain are highly interconnected, it is not difficult to find possible integrative frame-works between two or more of the various theo-ries. Testing the theories in a manner that can re-
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Summ a r y
It would be appealing to attempt to categorize de-pression in terms of monoamine-depletion forms that are perhaps related to genes coding for en-zymes involved in neurotransmission and cortisol-related forms that are characterized by a more long-term course, hippocampal atrophy, and a his-tory of psychosocial stress. However, the clinical data do not fall into such neat categories, since monoamine-based antidepressants are most effec-tive in patients with severe depression when cor-tisol levels remain high after the administration of dexamethasone.
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from endothelial dysfunction.128 Patients in their late teens or early 20s who have severe depression may have important genetic risk factors and a high risk of manic episodes.8 In patients with an anx-ious and depressive personality, depression may be due to genetically determined personality fac-tors11 or adverse childhood experiences.129
Avoidance of premature closure on any one scientific theory of the mechanism of depression will best serve the search for new, more effective treatments. It is likely that the pathogenesis of acute depression is different from that of recurrent or chronic depression, which is characterized by long-term declines in function and cognition. Mood can be elevated (by stimulants,46 by brain stimulation,123 or by ketamine94) or depressed (by monoamine depletion19 in recovered patients) for short periods, but longer-term improvement may require reduction of the abnormal glucocorticoid function induced by stress or increases in brain neurotrophic factors.
No potential conflict of interest relevant to this article was reported.
We thank Herman van Praag, who inspired our work on de-pression over the course of three decades.
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